tbuckley/cabot-search huggingface dataset:
Racial disparities in commercial U.S. oocyte donors.
Authors: Abigail Combs, Mariah J. Kimes, Carolyn Jaslow, Heidi Hayes, Lindsey B. O'Leary, Michael J. Levy, William H. Kutteh
Journal: Journal of Clinical Oncology (2022)

e18501 Background: Patients undergoing cancer treatment are more likely to face infertility. Despite improvements in counseling and fertility preservation, some oncology patients will require the use of donor oocytes to complete their family. We investigated whether the current cohort of commercial oocyte donors reflects the racial profile of the U.S. population. We also evaluated whether there were differences in donors’ perception of pain and quality of informed consent by race to elucidate potential avenues to improve donor retention. Methods: Institutional Review Board approved, retrospective survey of commercial, U.S. oocyte donors was emailed to recent donors recruited through Donor Egg Bank USA prior to 2020. There were 246 respondents out of 503 opened emails (48.9%). Donors were recruited by twenty different clinics that are affiliated with the same donor egg bank. Results: Black and Hispanic donors were significantly underrepresented among commercial U.S. egg bank donors while Caucasian and mixed-race donors were overrepresented (Table - left). The perception of pain in donors, however, did not differ according to race (Table - right, p = 0.245). Over 80% of donors reported that they had received better than acceptable levels of preparation through the informed consent process. Respondents’ report of the quality of the informed consent process did not differ by race (p = 0.728). Conclusions: Our study represents one of the largest cohorts of recent U.S. oocyte donors. The racial composition of recruited donors overrepresents Caucasian and mixed-race donors while underrepresenting Hispanic and Black donors when compared to the racial identity self-reported in the 2020 US census. This may represent the demographics of the current recipient cohort; however, the lack of diversity is of particular concern for oncology patients seeking oocytes as their racial composition likely reflects the diversity represented in the U.S. population. Notably, there was no difference by race in the pain score of donors by race or the quality of their informed consent process suggesting that all donors were treated similarly regardless of racial identity. Donor egg banks should consider diversification of their donor profiles to provide equal access among oncology patient seeking donor oocytes.[Table: see text]
NFB-05. A family-centered neurocutaneous syndrome clinic in the age of targeted therapies
Authors: Asher Marks, Richard Antaya, Lyn Balsamo, Kathleen Cardinale, Rebecca Cheron, David Frumberg, Victoria Gentile, Larissa Habib, Vidya Puthenpura, Hui Zhang
Journal: Neuro-Oncology (2022)

Abstract On April 10, 2020, the FDA approved selumetinib for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. This, combined with the 2016 EXIST-3 data showing the efficacy of adjunctive everolimus in the treatment of tuberous sclerosis associated seizures, have resulted in the re-imagining of the treatment of these neurocutaneous syndromes and subsequently, the multidisciplinary clinics in which they are treated. In early 2021, this reshaping resulted in the launch of a unique, family-centered clinic at Yale New Haven Children’s Hospital serving children and young adults up to 30 years of age in the management of NF1, NF2, tuberous sclerosis and schwannomatosis. Here we present the clinical reasoning and benefit of a multidisciplinary, family-centered clinic that manages to combine on-site, real-time access to neuro-oncology, neurology, psychology, dermatology, orthopedics, genetics, and ophthalmology. We will describe how the collaboration of these specialists is essential for providing high-quality, easy-access care to patients and families with the above noted syndromes – particularly with the advent of effective, readily available targeted therapies that carry their own side effects requiring further subspecialty consultation. Furthermore, we will describe previous and ongoing challenges to the creation of such a clinic and offer solutions based on our experience.
Characterization of <i>MET</i> exon 14 skipping alterations (<i>MET</i>ex14) in non–small cell lung cancer (NSCLC) using whole transcriptome sequencing (WTS).
Authors: So Yeon Kim, Stephen Bohlman, Jun Yin, Haiying Cheng, Phillip Walker, Sanja Dacic, Chul Kim, Hina Khan, Stephen V. Liu, Patrick C. Ma, Misako Nagasaka, Karen L. Reckamp, Jim Abraham, Dipesh Uprety, Balazs Halmos
Journal: Journal of Clinical Oncology (2022)

9122 Background: Multiple DNA alterations in exon 14 splice sites have been identified in NSCLC and result in skipping of the juxtamembrane domain Cbl-E3 ubiquitin ligase binding region, leading to increased MET stability and oncogenesis. The effects of these alterations on transcriptome-level have not been fully characterized. We present the largest cohort study of METex14 using WTS and identify key cellular pathways associated with invasion and metastases in METex14. Methods: 17,666 NSCLC tumor samples underwent genomic profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, WTS). METex14 was captured via WTS. ssGSEA analysis was used to evaluate pathway enrichment. Wilcoxon, Fisher’s exact were used for statistical significance (p without and q values with multiple comparison correction). Results: 440 patients (2.5%) with METex14 were identified. METex14 patients were of older age, female gender, and enriched in sarcomatoid histology (Table 1). The most common alterations were point mutations (51.5%) and deletions (17.3%) at donor splice sites. Splice site alterations except point mutations at splice acceptor site translated to increased mRNA expression compared to wild-type MET (WT). MET amplification translated to higher mRNA expression compared to METex14 and WT with synergistic expression when co-altered with METex14 (q&lt;0.05). The most common co-alterations were amplifications of MDM2 (18.5% vs. 1.8% WT), HMGA2 (13.7% vs 0.9% WT), and CDK4 (10.4% vs 1.4% WT) (q &lt; 0.05). METex14 were mutually exclusive to mutations in KRAS and EGFR. High PD-L1 (22c3) &gt; 50% (53% vs. 27.6% WT, q&lt;0.001) and lower TMB (4 mut/Mb vs. 7 mut/Mb WT, p&lt;0.001) were observed with METex14 and pathways associated with skipping variants included IFNγ signaling, angiogenesis, and apical junction pathways on univariate analysis (q&lt;0.05). Conclusions: We present the largest WTS analysis of METex14. Splicing alterations and MET co-amplification translated to higher and synergistic MET expression at transcriptome level, respectively. Association with upregulated angiogenic and apical junction pathways support preclinical observation of vascular and cytoskeletal remodeling as potential mechanisms of invasion and metastases in MET ex14 NSCLC.[Table: see text]
Outcomes of patients with advanced urothelial cancer who develop infection while on treatment with pembrolizumab.
Authors: Ryan Blair Kieser, Jiaqiong Xu, Ethan Burns, Ibrahim Muhsen, Shivan M Shah, Godsfavour Umoru, Charisma Mylavarapu, Kai Sun, Yuqi Zhang, Aubrey Crenshaw, Abdullah Esmail, Carlo Guerrero, Zimu Gong, Kelly Gee, Kirk Heyne, Monisha Singh, Jun Zhang, Eleni Efstathiou, Eric Bernicker, Maen Abdelrahim
Journal: Journal of Clinical Oncology (2022)

4573 Background: Over the past decade, studies have shown the benefit of immune checkpoint inhibitors (IO) in patients with advanced urothelial cancer. These agents work by reconditioning the adaptive anti-cancer immune response within the tumor microenvironment. Immune-related adverse events have been well documented, but there is limited data evaluating infections in patients treated with IO. We performed a retrospective analysis to assess the incidence of infection and its effect on morbidity and mortality in patients treated with pembrolizumab for advanced urothelial cancer. Methods: Data was collected from a network of 7 hospitals for patients who received pembrolizumab for advanced urothelial cancer from 1/1/2017-8/1/2021. Date of last follow up was 12/1/2021. Covariates compared among infected and non-infected cohorts included age, gender, race, comorbidities, ECOG, anti-infective therapy at IO initiation, and line of therapy (1L, 2L, &gt; 2L). Univariable analysis with reported odds ratio (OR) and 95% confidence interval (CI) was used to assess risk factors for infection. Outcome measures included all-cause emergency department (ED) visits, inpatient and intensive care unit (ICU) admissions, median number of IO cycles, and overall survival (OS). OS was evaluated using the Kaplan-Meier model. All analyses were deemed statistically significant if the p-value was &lt; 0.05. Results: A total of 51 patients were identified. Of these, 34 (66.7%) had at least one documented infection and 17 (33.3%) had no reported infections. Baseline characteristics were similar across cohorts. Compared to non-infected patients, infected patients received fewer cycles of IO (median 4 vs 8, p = 0.016). At last follow-up, 20 (58.8%) patients in the infected cohort and 4 (23.5%) in the non-infected cohort died (p = 0.017). Median OS was 7.4 months (95% CI: 3.4-24.9) among patients with infection while not reached in those without infection (p = 0.014). ED visits (p = 1.00), inpatient admissions (p = 0.21), and ICU admissions (p = 0.17) did not significantly differ between cohorts. Univariable analysis did not identify significant risks among covariates. Conclusions: The incidence of infection in patients treated with pembrolizumab for advanced urothelial cancer is high and associated with fewer cycles of IO therapy and shorter OS. Further study of infectious process prevention is of value to maximize immunotherapy benefit.
Newly identified molecular and genetic characteristics of primary mediastinal large B-cell lymphoma.
Authors: Inna A. Kamaeva, Inna A. Novikova, Irina B. Lysenko, Natalya N. Timoshkina, Nadezhda V. Nikolaeva, Elena A. Kapuza, Yakha S. Gaysultanova, Tatiana F. Pushkareva, Anna V. Tishina, Natalia Yu. Samaneva, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2022)

e19580 Background: Many studies have been devoted to the molecular profile of diffuse large B-cell lymphoma; however, a clear molecular and genetic picture of primary mediastinal large B-cell lymphoma (PMBLC) has not yet been described. Studies have reported various signaling pathways involved in PMBCL pathogenesis, with the best known JAK-STAT and NF-kB. This study was aimed at the detection of previously undescribed mutations, as well as the identification of signaling pathways that may be of interest in the search for new therapeutic targets for PMBCL. Methods: Tumor biopsy specimens from 23 PMBCL patients were examined by next-generation sequencing (NGS) on the Illumina NextSeq 550 system with an average coverage of at least 100x using the AVENIO Tumor Expanded Panel (Roche, USA) containing 77 genes. Analytical sensitivity of mutation detection was 5%. The pathogenicity of the identified nucleotide substitutions was assessed according to ACMG (American College of Medical Genetics and Genomics) and AMP (Association of Molecular Pathology) recommendations. Genomic DNAs were extracted from FFPE blocks using the Gene Read DNA FFPE Kit panel (Qiagen, USA) according to the standard protocol. DNA concentrations were measured fluorimetrically on the Qubit 2.0 fluorometer (Life Technologies, USA). The AVENIO Oncology Analysis Software was used to process the data and to search for clinically significant mutations. The genetic material was analyzed for clinically significant mutations among well-known databases: COSMIC: V83, TCGA 9.0, Exac: 1.0, DBSNP: 150, 1000 Genomes: phase_3_v5b, Snpeff: 4.2. Results: The targeted high-performance sequencing of PMBLC samples showed a newly revealed range of polymorphisms in 9 genes in patients with PMBLC (Alk, TP53, CCND3, RNF43, PIK3CA, FGFR3, SMO, MET, EZH2), previously not described for this cancer. We also interpreted signal pathways related to the mutated genes. Conclusions: The identified polymorphisms and the relationship of mutated genes with PMBLC signaling paths can serve as new therapeutic targets for patients with PMBLC.
Spatiotemporal distribution of liver cancer mortality rate in Peru between 2003-2017.
Authors: Claudio J. Flores, Mariano Francisco Lopez Pereyra, Luis Chirinos, Pamela Carrion, Daniel Enriquez
Journal: Journal of Clinical Oncology (2022)

e22521 Background: Liver cancer represents the sixth most frequent neoplasm and the third leading cause of cancer death worldwide, although it possesses an heterogenous incidence and mortality. In Peru, its mortality rate distribution is unknown. We aimed to explore the spatio-temporal distribution of liver cancer mortality rate according to Peruvian geographical regions. Methods: We obtained data from liver cancer deaths between 2003-2017 from the Peruvian Ministry of Health Registry. Population data was obtained from The National Institute of Statistics and Informatics (INEI, Peru). Age-standardized mortality rate (ASMR) was calculated based on the 2011 world standard populations. Spatial autocorrelation was determined according to Moran’s Index and the Local G Cluster Map to explore the cluster patterns between regions. Results: During the study period, 18,427 deaths for liver cancer were reported on the national death system. The liver cancer mortality rate in Peru increased from an ASMR of 4.1 (95% CI: 3.4, 4.8) in 2003 to 4.4 (95% CI: 3.8, 5.0) in 2017, with an average mortality rate of 4.9 (95% CI: 4.6, 5.2) by 100 000 persons-year. According to the political regions of Peru, the mortality rate distribution showed a spatial variation (ASMR of 0.6 to 12.2 per 100 000 persons-year); the mortality rate was high in coast regions and low among highlands regions. The ASMR spatial distribution showed a significant spatial autocorrelation (Moran’s I: p &lt; 0.05). During the study period, the ASMR showed a significant increasing and decreasing mortality in several geographic regions and remained constant in other regions. Conclusions: In Peru, the liver cancer mortality rate shows a spatial and temporal variation according to geographical regions. The increase in the mortality rate in some regions requires further identification of local risk factors to implement programs aimed at reducing incidence and mortality.
A national inpatient sample analysis for CAR-T cell therapy administration.
Authors: Veli Bakalov, Amy Tang, Alexander M Helfand, Pragnan Kancharla, Richard White, Ahmed Khattab, Mohammad Alhousani, Yazan Samhouri
Journal: Journal of Clinical Oncology (2022)

e19501 Background: Chimeric antigen receptor T-cell therapies (CAR-T) improve relapse free survival and durable remission rates in patients with relapsed/refractory large B-cell lymphoma (LBCL) and received US FDA approval in 2017. The cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity (ICANS) due to CAR-T cell therapy require close inpatient monitoring. Real world data are lacking regarding the cost of hospitalization, length of stay (LOS), toxicity, and mortality associated with CAR-T. The goal of this study was to analyze the clinical outcomes of inpatient CAR-T utilizing a national database. Methods: Data was collected from the 2018 version of the Nationwide Inpatient Sample (NIS) database. Patients who received CAR-T were identified with ICD-10 disease and procedure codes . Complex weights were used to enable appropriate national projections. The association between toxicity (particularly related to CRS and ICANS) and outcomes was examined using logistic regression analyses (p &lt; 0.05 statistically significant). SAS v9.4 (SAS Institute, Cary, NC) was used for data analysis. Results: 306 patients met selection criteria. Demographic criteria were as follows: 61.1% males, 62.4% white, median age 58.0 years old (IQR 45.2-65.0), and private insurance (56.9%). A majority received care at urban teaching (97.7%) and large hospitals (73.2%). Relevant complications during hospitalization included hypotension (24.5%), pneumonia (8.5%), sepsis (9.8%), seizure (5.9%), neutropenia (24.5%), thrombocytopenia (8.8%), tumor lysis syndrome (TLS) (3.3%), and acute kidney injury (AKI) (14.1%). Median LOS was 16 days (IQR 12.0-22.0), median charge for hospitalization was $493,887 USD (IQR 143,400.0-1,182,940.0), and inpatient mortality was 5.2%. On multivariate regression analysis, inpatient mortality was significantly higher in those with intubation (OR 30.1, 95%CI 3.45-262), sepsis (OR 9.49, 95%CI 1.48-60.7), TLS (OR 18.9, 95%CI 2.52-140), AKI (OR 24.7, 95% CI 1.37-447) and thrombocytopenia (OR 53.4, 95% CI 2.19-1,298). LOS was higher in those with blood transfusion (OR 1.29, 95% CI 1.08-1.53), sepsis (OR 2.04, 95% CI 1.59-2.61), pancreatitis (OR 2.03, 95% CI 1.09-3.77), pneumonia (OR 1.39, 95%CI 1.04-1.87) and treatment in urban teaching hospitals (OR 1.53, 95%CI 1.02-2.30). Increased hospitalization charges were associated with hypotension (OR 1.54, 95%CI 1.14-2.08) and with treatment at urban teaching hospitals (OR 7.46, 95%CI 4.67-11.9) and medium size hospitals (OR 1.49, 95%CI 1.04-2.15). Conclusions: Inpatient mortality, median LOS, and hospitalization charges in inpatients treated with CAR-T can be significantly increased not only by inpatient complications, but also by the size and type of the treating facility. These findings highlight the financial burden of CAR-T cell therapy in the real world and can be used to shape future healthcare policy.
DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity
Authors: Alexander Muik, Homer C Adams, Friederike Gieseke, Isil Altintas, Kristina B Schoedel, Jordan M Blum, Bianca Sänger, Saskia M Burm, Eliana Stanganello, Dennis Verzijl, Vanessa M Spires, Fulvia Vascotto, Aras Toker, Juliane Quinkhardt, Mark Fereshteh, Mustafa Diken, David P E Satijn, Sebastian Kreiter, Tahamtan Ahmadi, Esther C W Breij, Özlem Türeci, Kate Sasser, Ugur Sahin, Maria Jure-Kunkel
Journal: Journal for ImmunoTherapy of Cancer (2022)

Despite the preclinical promise of CD40 and 4-1BB as immuno-oncology targets, clinical efforts evaluating CD40 and 4-1BB agonists as monotherapy have found limited success. DuoBody-CD40×4-1BB (GEN1042/BNT312) is a novel investigational Fc-inert bispecific antibody for dual targeting and conditional stimulation of CD40 and 4-1BB to enhance priming and reactivation of tumor-specific immunity in patients with cancer.
PATH-10. Nanopore sequencing reveals novel ALK fusion with interposed element in a neonate with hemispheric glioma
Authors: Anthony P Y Liu, Chris T L Chan, Edmond S K Ma, Wilson W S Ho, Dennis T L Ku, Matthew M K Shing, Amanda N C Kan, Godfrey C F Chan, Ho-Keung Ng
Journal: Neuro-Oncology (2022)

Abstract Here we describe the clinical course and unique molecular findings in a female neonate with infantile hemispheric glioma (IHG). The patient presented at the age of 17 days with macrocephaly and suboptimal weight gain. MRI brain revealed an 8.5cm mass over the right frontal region with significant mass effect and entrapment of ventricles. Urgent ventriculoperitoneal shunt insertion and biopsy of the highly vascular lesion was performed. Pathology was compatible with glioblastoma multiforme. Methylation profiling classified the sample as inflammatory tumor tissue (MNP v11b4), while panel RNA-sequencing revealed a fusion event between HMBOX1 and ALK which has not been described in primary CNS tumors. Long-read sequencing with the Nanopore system further revealed complex genomic rearrangement involving an interposed genomic fragment from a third chromosome with validation by Sanger sequencing. Based on an integrated diagnosis of IHG, the patient went on to receive neoadjuvant chemotherapy per the CNS-14 protocol (cyclophosphamide, carboplatin, etoposide) with significant tumor shrinkage. Near total removal of the lesion was achieved after 4 cycles of chemotherapy and adjuvant treatment with 4 additional cycles was given. The patient tolerated therapy well other than self-limiting transaminitis. At the end of treatment, the patient enjoyed intact neurology and satisfactory developmental progress. Our case report illustrates the value a multi-pronged approach to characterizing rare pediatric CNS tumors. The precise delineation of breakpoints in fusion-driven tumors might be of value in the design of cfDNA-based assays. (APYL and CTLC contributed equally to the submission)
Effectiveness and safety of retreatment with lutetium Lu 177 DOTATATE in patients with progressive neuroendocrine tumors in the United States: A retrospective real-world study.
Authors: Ebrahim Delpassand, Soheil Mohammadi Yazdi, Shashank Ghantoji, Antonio Reis Nakasato, Corinne Denise Strickland, Rodolfo Nunez, Afshin Shafie, Susan Cork, Clare Byrne, Jackson Tang, Kyle Runeckles, Jeetvan Patel
Journal: Journal of Clinical Oncology (2022)

e16215 Background: Advanced neuroendocrine tumors (NETs) are associated with a very poor prognosis. A regimen of 4 doses of lutetium Lu 177 ( 177 Lu)-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients with advanced NETs. This is the first United States (US) study to evaluate the effectiveness and safety of additional doses in patients with progressive NETs. Methods: This was a retrospective chart review of 31 adults with advanced NETs who had undergone initial treatment with up to 4 doses of 177 Lu-DOTATATE and who, following disease progression and a period of ≥6 months since the end of initial treatment, were re-treated with ≥1 additional dose at a single US center (2010–2020). Patient characteristics, treatment patterns, and clinical outcomes were evaluated descriptively. Response was evaluated according to RECIST 1.1; toxicity was defined using CTCAE 5.0 criteria. Kaplan–Meier plots were used to evaluate PFS and OS. Results: Of the 31 patients who received 177 Lu-DOTATATE re-treatment, 19 (61%) were male and 29 (94%) were white. Overall, patients received a median of 6 doses (4 initial doses and 2 re-treatment doses) and the mean±sd administered activity was 41.9±4.4 GBq. Two patients also went on to receive additional re-treatment (1 and 2 doses, respectively) following a second period of ≥6 months and progression after re-treatment. Best responses of partial response and stable disease were observed in 11 patients (35%) and 20 patients (65%) after initial treatment, and 7 patients (23%) and 14 patients (45%) after re-treatment (Table). The median PFS after initial treatment was 20.2 months and after re-treatment was 9.6 months. The median OS after initial treatment was 42.6 months and after re-treatment was 12.6 months. Hematological parameters decreased significantly during both initial and re-treatment but recovered such that there was no significant difference between the values prior to initial treatment and prior to re-treatment. Clinically significant hematotoxicity occurred in 1 and 3 patients following initial and re-treatment, respectively. No grade 3/4 nephrotoxicity (based on creatinine levels) was observed. Conclusions: Re-treatment with 177 Lu-DOTATATE after progression appeared to be well-tolerated and offered disease control in patients with progressive NETs following initial 177 Lu-DOTATATE treatment.[Table: see text]